Pharmgenomics Pers Med. 2023 Jul 11;16:729-737. doi: 10.2147/PGPM.S361222. eCollection 2023.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

PMID:37457231 | PMC:PMC10349598 | DOI:10.2147/PGPM.S361222

iScience. 2023 Jun 15;26(7):107130. doi: 10.1016/j.isci.2023.107130. eCollection 2023 Jul 21.

ABSTRACT

Hydrochlorothiazide (HCTZ) is reported to impair glucose tolerance and may induce new onset of diabetes, but the pharmacomicrobiomics of the adverse effect for HCTZ remains unknown. Mice-fed HCTZ exhibited insulin resistance and impaired glucose tolerance. By using FMT and antibiotic cocktail models, we found that HCTZ-induced metabolic disorder was mediated by commensal microbiota. HCTZ consumption disturbed the structure of the intestinal microbiota, causing abnormal elevation of Gram-negative Enterobacteriaceae and lipopolysaccharide (LPS) then leading to intestinal barrier dysfunction. Additionally, HCTZ activated TLR4 signaling and induced macrophage polarization and inflammation in the liver. Furthermore, HCTZ-induced macrophage polarization and metabolic disorder were abrogated by blocking TLR4 signaling. HCTZ consumption caused a significant increase in Gram-negative Enterobacteriaceae, which elevated the levels of LPS, thereby activating LPS/TLR4 pathway, promoting inflammation and macrophage polarization, and resulting in metabolic disorders. These findings revealed that the gut microbiome is the key medium underlying HCTZ-induced metabolic disorder.

PMID:37456847 | PMC:PMC10338205 | DOI:10.1016/j.isci.2023.107130

Hum Genomics. 2023 Jul 15;17(1):63. doi: 10.1186/s40246-023-00509-0.

ABSTRACT

INTRODUCTION: The adoption and implementation of genomic medicine and pharmacogenomics (PGx) in healthcare systems have been very slow and limited worldwide. Major barriers to knowledge translation into clinical practice lie in the level of literacy of the public of genetics and genomics. The aim of this study was to assess the knowledge, attitudes, and perceptions of the United Arab Emirates (UAE) multi-ethnic communities toward genomic medicine and genetic testing.

METHOD: A cross-sectional study using validated questionnaires was distributed to the participants. Descriptive statistics were performed, and multivariable logistic regression models were used to identify factors associated with knowledge of genomics.

RESULTS: 757 individuals completed the survey. Only 7% of the participants had a good knowledge level in genetics and genomics (95% CI 5.3-9.0%). However, 76.9% of the participants were willing to take a genetic test if their relatives had a genetic disease. In addition, the majority indicated that they would disclose their genetic test results to their spouses (61.5%) and siblings (53.4%).

CONCLUSIONS: This study sets the stage for the stakeholders to plan health promotion and educational campaigns to improve the genomic literacy of the community of the UAE as part of their efforts for implementing precision and personalized medicine in the country.

PMID:37454085 | DOI:10.1186/s40246-023-00509-0

Hum Genomics. 2023 Jul 14;17(1):62. doi: 10.1186/s40246-023-00508-1.

ABSTRACT

BACKGROUND: This pilot study aims to identify and functionally assess pharmacovariants in whole exome sequencing data. While detection of known variants has benefited from pharmacogenomic-dedicated bioinformatics tools before, in this paper we have tested novel deep computational analysis in addition to artificial intelligence as possible approaches for functional analysis of unknown markers within less studied drug-related genes.

METHODS: Pharmacovariants from 1800 drug-related genes from 100 WES data files underwent (a) deep computational analysis by eight bioinformatic algorithms (overall containing 23 tools) and (b) random forest (RF) classifier as the machine learning (ML) approach separately. ML model efficiency was calculated by internal and external cross-validation during recursive feature elimination. Protein modelling was also performed for predicted highly damaging variants with lower frequencies. Genotype-phenotype correlations were implemented for top selected variants in terms of highest possibility of being damaging.

RESULTS: Five deleterious pharmacovariants in the RYR1, POLG, ANXA11, CCNH, and CDH23 genes identified in step (a) and subsequent analysis displayed high impact on drug-related phenotypes. Also, the utilization of recursive feature elimination achieved a subset of 175 malfunction pharmacovariants in 135 drug-related genes that were used by the RF model with fivefold internal cross-validation, resulting in an area under the curve of 0.9736842 with an average accuracy of 0.9818 (95% CI: 0.89, 0.99) on predicting whether a carrying individuals will develop adverse drug reactions or not. However, the external cross-validation of the same model indicated a possible false positive result when dealing with a low number of observations, as only 60 important variants in 49 genes were displayed, giving an AUC of 0.5384848 with an average accuracy of 0.9512 (95% CI: 0.83, 0.99).

CONCLUSION: While there are some technologies for functionally assess not-interpreted pharmacovariants, there is still an essential need for the development of tools, methods, and algorithms which are able to provide a functional prediction for every single pharmacovariant in both large-scale datasets and small cohorts. Our approaches may bring new insights for choosing the right computational assessment algorithms out of high throughput DNA sequencing data from small cohorts to be used for personalized drug therapy implementation.

PMID:37452347 | DOI:10.1186/s40246-023-00508-1

Eur J Pharm Sci. 2023 Jul 12:106527. doi: 10.1016/j.ejps.2023.106527. Online ahead of print.

ABSTRACT

Reduced activity of efflux transporter ABCG2, caused e.g., by inhibition or decreased function genetic variants, can increase drug absorption and plasma levels. ABCG2 has one clinically significant single nucleotide variant Q141K (c.421C>A), which leads to decreased protein levels and transport activity. In addition to Q141K, ABCG2 has over 500 rare (<1% minor allele frequency) nonsynonymous variants, but their functionality remains unknown. We studied the transport activity and abundance of 30 rare ABCG2 variants. The variants were transiently expressed in HEK293 cells. Transport activity and protein abundance were measured from inside-out crude membrane vesicles. Results were normalised to the reference ABCG2 while Q141K was used to categorise variants into decreased and normal function phenotypes based on their apparent transport activity. Fourteen variants (G80E, D128V, T434M, Q437R, C438R, C438W, C438Y, L479S, P480L, S486N, T512N, S519P, G553D and K647E) had similar or lower apparent transport activity than Q141K and thus were categorised as having a decreased function phenotype. Protein abundance could not explain all of the observed changes in transport activity: Only six variants (D128V, Q437R, C438R, S519P, G553D, and K647E) had similar or lower abundance compared to Q141K. The decreased function variants may increase systemic drug exposure and therefore cause interindividual variability in pharmacokinetics. In the future, in vitro phenotype classification may help to design personalised drug treatments.

PMID:37451410 | DOI:10.1016/j.ejps.2023.106527

Annu Rev Pharmacol Toxicol. 2023 Jul 14. doi: 10.1146/annurev-pharmtox-030823-111731. Online ahead of print.

ABSTRACT

The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcase CYP2D6, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37450899 | DOI:10.1146/annurev-pharmtox-030823-111731

JCO Oncol Pract. 2023 Jul 14:OP2300227. doi: 10.1200/OP.23.00227. Online ahead of print.

ABSTRACT

Cancer therapy has environmental costs. In this simulation analysis, @garthstrohbehn and colleagues show how less frequent dosing and shorter durations of therapy might improve public health without making patients with cancer worse off.

PMID:37450776 | DOI:10.1200/OP.23.00227

Per Med. 2023 Jul 14. doi: 10.2217/pme-2022-0122. Online ahead of print.

ABSTRACT

The biggest challenges that any country faces are affordability and accessibility of quality healthcare. Technological advancements can address these challenges. One such advancement is personalized medicine (PM). This paper discusses the implementation and institutionalization of PM. Using the sectoral innovation system framework, this work describes government interventions with research trends in PM in India. The Web of Science database was used to analyze research trends. Indian government-funded interventions to institutionalize PM were compiled and analyzed. Results suggest that India's healthcare sector is dynamic. The framework discusses some specifics, including the research network, boundaries and government initiatives to promote PM adoption. Based on the policy gaps, this paper further proposes an integrated policy framework for incorporating PM into India's healthcare system.

PMID:37449373 | DOI:10.2217/pme-2022-0122

Front Pediatr. 2023 Jun 28;11:1168619. doi: 10.3389/fped.2023.1168619. eCollection 2023.

ABSTRACT

Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates <2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control.

PMID:37449265 | PMC:PMC10337585 | DOI:10.3389/fped.2023.1168619

J Empir Res Hum Res Ethics. 2023 Jul 13:15562646231187434. doi: 10.1177/15562646231187434. Online ahead of print.

ABSTRACT

Little is known about whether people living with HIV would like to receive their results from pharmacogenomics research. This study explored the factors influencing participants' preferences and the reasons for their desire to receive individual results from pharmacogenomics research. We employed a convergent parallel mixed methods study design comprising a survey of 225 research participants and 5 deliberative focus group discussions with 30 purposively selected research participants. Almost all (98%) participants wanted to receive individual pharmacogenomics research results. Reasons for the desire to receive results were reciprocity for valuable time and effort, preparing for future eventualities, and the right to information about their health. Overall, participants desire to receive feedback from pharmacogenomics research, particularly if results are well established and clinically actionable.

PMID:37448227 | DOI:10.1177/15562646231187434

Molecules. 2023 Jun 28;28(13):5055. doi: 10.3390/molecules28135055.

ABSTRACT

Nonaqueous capillary electrophoretic (NACE) separation was obtained of analogs of (24R)-1,24-dihydroxyvitamin D3 derivative (calcipotriol) as predicted by quantum chemical calculations supported by the density functional theory (DFT). Among the key electronic properties investigated, absolute values of the dipole polarizability and energy gap between HOMO and LUMO molecular orbitals of the analog molecules differ significantly for particular analogs, and there is a direct relationship with their electrophoretic migration time. These differences and relationships suggest that the structurally related analogs should be separable in the electrostatic field. Indeed, the robust, sensitive, and rapid NACE method was first developed for the identification and determination of the anticancer analog of calcipotriol (coded PRI-2205) and its process-related impurities (coded PRI-2201, PRI-2203, and PRI-2204) in organic and aqueous biological solutions. The direct relation between the calculated electronic properties of the analogs and the experimental electrophoretic migration time could be a promising prospect for theoretically predicting the electrophoretic separations.

PMID:37446718 | DOI:10.3390/molecules28135055

Int J Mol Sci. 2023 Jun 28;24(13):10754. doi: 10.3390/ijms241310754.

ABSTRACT

Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n = 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided by CYP2D6, μ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1-5] vs. 1 [0-2], p < 0.01) and 42% opioid dose (35 [22-61] vs. 60 [40-80] mg/day, p < 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58-0.82] vs. 0.51 [0.13-0.67] controls, p < 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30-34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation.

PMID:37445931 | DOI:10.3390/ijms241310754

J Clin Med. 2023 Jul 3;12(13):4454. doi: 10.3390/jcm12134454.

ABSTRACT

Kidney transplantation is the preferred therapeutic option for end-stage kidney disease, but, despite major therapeutic advancements, allograft rejection continues to endanger graft survival. Every patient is unique due to his or her clinical history, drug metabolism, genetic background, and epigenetics. For this reason, examples of "personalized medicine" and "precision medicine" have steadily increased in recent decades. The final target of precision medicine is to maximize drug efficacy and minimize toxicity for each individual patient. Immunosuppressive drugs, in the setting of kidney transplantation, require a precise dosage to avoid either adverse events (overdosage) or a lack of efficacy (underdosage). In this review, we will explore the knowledge regarding the pharmacogenomics of the main immunosuppressive medications currently utilized in kidney transplantation. We will focus on clinically relevant pharmacogenomic data, that is, the polymorphisms of the genes that metabolize immunosuppressive drugs.

PMID:37445489 | DOI:10.3390/jcm12134454

J Clin Med. 2023 Jun 21;12(13):4192. doi: 10.3390/jcm12134192.

ABSTRACT

Background and aims: Autoimmune hepatitis (AIH) is a complex and progressive inflammatory liver disease characterized by immune-mediated destruction of the liver parenchyma, hypergammaglobulinemia, the presence of circulating autoantibodies, and good response to immunosuppressive therapy. Since the prevalence of AIH is relatively rare, data on the clinical course and the long-term outcome are scarce. Patients and methods: We retrospectively analyzed the data of 535 well-documented AIH patients treated at the University Hospital Essen between 2000 and 2020. Results: The majority of patients were middle-aged females (75% women, mean age 45 years) with AIH type 1 (97%). Approximately 32% of patients were diagnosed with cirrhosis due to AIH, 29% had concomitant autoimmune (predominantly autoimmune thyroiditis), and 10% had psychiatric diseases, respectively. Skin tumors were the most common malignant diseases (47% of all tumors), while hepatocellular carcinoma rarely occurred (only six cases). Overall long-term mortality and liver-associated mortality were 9.16% and 4.67%, respectively. However, long-term survival was strongly associated with disease remission. Conclusions: Although AIH is a silent disease and cirrhosis is present in many cases, a favorable long-term prognosis can be achieved by consequent immunosuppressive therapy. The incidence of (liver-associated) complications seems to be lower in comparison to other etiologies, such as viral hepatitis or NASH, and mainly depends on the long-term side effects of immunosuppressive therapy.

PMID:37445225 | DOI:10.3390/jcm12134192

Cancers (Basel). 2023 Jun 22;15(13):3289. doi: 10.3390/cancers15133289.

ABSTRACT

BACKGROUND: Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach.

METHODS: High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma. RNAseq analysis supplemented this 128-compound screening to predict more efficacious and patient-specific drug combinations with additional tumor stemness evaluated using flow cytometry. In vivo PDX mouse models rapidly validated (50 days) and determined mutational influence alongside of drug efficacy. We present a representative GBM case of three tumors resected at initial presentation, at first recurrence without any treatment, and at a second recurrence following radiation and chemotherapy, all from the same patient.

RESULTS: Molecular and in vitro screening helped identify effective drug targets against several pathways as well as synergistic drug combinations of cobimetinib and vemurafenib for this patient, supported in part by in vivo tumor growth assessment. Each tumor iteration showed significantly varying stemness and drug resistance.

CONCLUSIONS: Our integrative model utilizing molecular, in vitro, and in vivo approaches provides direct evidence of a patient's tumor response drifting with treatment and time, as demonstrated by dynamic changes in their tumor profile, which may affect how one would address that drift pharmacologically.

PMID:37444398 | DOI:10.3390/cancers15133289

Phytother Res. 2023 Jul 13. doi: 10.1002/ptr.7942. Online ahead of print.

ABSTRACT

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES-2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti-angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

PMID:37443453 | DOI:10.1002/ptr.7942

Clin Pharmacokinet. 2023 Jul 13. doi: 10.1007/s40262-023-01270-2. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS).

METHODS: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an Emax model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated.

RESULTS: Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R0 = 43 nM), and complex elimination rate constant (kint = 0.95 day-1). Estimated time-varying clearance parameters were time-invariant component of CL (CL0= 0.38 L/day-1), time-variant component of CL (CL1= 0.058 L/day-1) and first-order rate of CL1 decreasing over time (kdes = 0.049 day-1). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP.

CONCLUSION: This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship.

PMID:37442917 | DOI:10.1007/s40262-023-01270-2

J Affect Disord. 2023 Jul 11:S0165-0327(23)00839-X. doi: 10.1016/j.jad.2023.07.007. Online ahead of print.

ABSTRACT

BACKGROUND: The optimal dosage and method of esketamine for postpartum depressive symptoms (PDS) are unclear. We conducted a randomized controlled trial (RCT) to investigate the effect of different doses of esketamine on PDS in women undergoing cesarean section, with evidence of prenatal depression.

METHODS: The three groups were high- (2 mg kg-1) and low-dose (1 mg kg-1) esketamine via patient controlled intravenous analgesia (PCIA), following an initial intravenous infusion of 0.25 mg kg-1 esketamine, compared to placebo (0.9 % saline infusion). All groups also received the sufentanil (2.2 μg kg-1). The primary outcome was the incidence of PDS at 7 and 42 days postpartum. The secondary outcomes were: the remission from depression and total EPDS scores at 7 days and 42 days postpartum; mean change from baseline in the EPDS score; postoperative analgesia.

RESULTS: i). 0.25 mg kg-1 of esketamine intravenous infusion combined with 1 mg kg-1 (n = 99) or 2 mg kg-1 (n = 99) esketamine PCIA reduces PDS incidence at 7 days postpartum (p < 0.05), with high-dose esketamine PCIA also reduces PDS incidence 42 days postpartum (p < 0.05), compared to placebo (n = 97). ii). Low- and high-dose esketamine PCIA lowers NRS scores at rest within 48 h postoperatively (p < 0.01), with high-dose esketamine also reducing the NRS score during movement at 48 h postoperatively (p = 0.018). iii). Neither high- nor low-dose esketamine PCIA increased postoperative adverse reactions (p > 0.05).

CONCLUSIONS: Esketamine (0.25 mg kg-1) intravenous infusion combined with 1 mg kg-1 or 2 mg kg-1 esketamine PCIA seems safe and with few adverse effects in the management of PDS and pain in women undergoing cesarean section.

LIMITATIONS: The tolerability and safety of esketamine requires further investigation based on more specific scales; the transient side effects of esketamine could have biased the staff and patients.

TRIAL REGISTRATION: ChiCTR-ROC-2000039069.

PMID:37442447 | DOI:10.1016/j.jad.2023.07.007

Neurohospitalist. 2023 Jul;13(3):256-265. doi: 10.1177/19418744231161390. Epub 2023 May 12.

ABSTRACT

INTRODUCTION: Breakthrough acute ischemic stroke (AIS) in patients with known, nonvalvular Atrial Fibrillation (AF), on Direct Oral Anticoagulants (DOAC), is an ongoing clinical conundrum. Switching anticoagulants was shown to be ineffective in preventing recurrent AIS. Systematic, patient-level chart review of so-called "DOAC failures" may offer insight into this phenomenon.

METHODS: We conducted an IRB-approved, 6-year, retrospective study of AIS admissions, already prescribed DOAC for known AF. We sought plausible, alternative reasons for the AIS using a novel classification schema, CLAMP: C for Compliance concerns, L for Lacunes (small-vessel disease), A for Arteriopathy (atherosclerosis, web, or vasculitis), M for Malignancy, and P for Patent Foramen Ovale (PFO). These categories were labeled as DOAC "Pseudo-failures." Conversely, absence of CLAMP variables were labeled as DOAC "Crypto-failures" conceivably from AF itself ("atriopathy") or pharmacokinetic/pharmacogenomic dysfunction (ie, altered DOAC absorption, clearance, metabolism, or genetic polymorphisms). Forward logistic regression analysis was performed on prespecified DOAC subgroups.

RESULTS: Of 4890 AIS admissions, 606 had AF, and 87 were previously prescribed DOAC (14.4% overall DOAC failure rate, 2.4% annualized over 6 years). Pseudo-failures comprised 77%: Compliance concerns (48.9%), Lacunes (5.7%), Arteriopathy (17.0%), Malignancy (26.1%), and PFO (2.3%). Crypto-failures comprised 23%, had lower CHADSVASc scores (AOR = .65, P = .013), and occurred more with rivaroxaban (41%) than apixaban (16%) or dabigatran (5.6%).

CONCLUSION: In AIS patients with known AF, DOAC Pseudo-failures, with identified alternate etiologies, are 3 times more likely than DOAC Crypto-failures. The CLAMP schema represents a novel approach to diagnostic classification and therapeutic adjustments in patients already prescribed DOAC for AF.

PMID:37441203 | PMC:PMC10334065 | DOI:10.1177/19418744231161390

Mol Cancer Ther. 2023 Jul 13:MCT-22-0486. doi: 10.1158/1535-7163.MCT-22-0486. Online ahead of print.

ABSTRACT

As a result of tumor heterogeneity and solid cancers harboring multiple molecular defects, precision medicine platforms in oncology are most effective when both genetic and pharmacological determinants of a tumor are evaluated. Expandable patient-derived xenograft (PDX) mouse tumor and corresponding PDX culture (PDXC) models recapitulate many of the biological and genetic characteristics of the original patient tumor, allowing for a comprehensive pharmacogenomic analysis. Here, the somatic mutations of 23 matched patient tumor and PDX samples encompassing four cancers were first evaluated using next generation sequencing (NGS). 19 antitumor agents were evaluated across 78 patient-derived tumor cultures using clinically relevant drug exposures. A binarization threshold sensitivity classification determined in culture (PDXC) was used to identify tumors that best respond to drug in vivo (PDX). Utilizing this sensitivity classification, logic models of DNA mutations were developed for 19 antitumor agents to predict drug response. We determined that the concordance of somatic mutations across patient and corresponding PDX samples increased as variant allele frequency (VAF) increased. Notable individual PDXC responses to specific drugs, as well as lineage-specific drug responses where identified. Robust responses identified in PDXC were recapitulated in vivo in PDX-bearing mice and logic modeling determined somatic gene mutation(s) defining response to specific antitumor agents. In conclusion, combining NGS of primary patient tumors, high-throughput drug screen (HTDS) using clinically relevant doses, and logic modeling, can provide a platform for understanding response to therapeutic drugs targeting cancer.

PMID:37440705 | DOI:10.1158/1535-7163.MCT-22-0486